Causes and pathophysiology of high-output heart failure

INTRODUCTION — While most patients with heart failure (HF), with either reduced or preserved ejection fraction, have low or normal cardiac output accompanied by elevated systemic vascular resistance, a minority of patients with HF present with a high-output state with low systemic vascular resistance.

This topic will discuss the causes and pathophysiology of high-output HF. Clinical manifestations, diagnosis, and management of high-output HF are discussed separately. (See "Clinical manifestations, diagnosis, and management of high-output heart failure".)

The diagnosis and management of HF with reduced ejection fraction and HF with preserved ejection fraction are discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

EPIDEMIOLOGY — High-output HF is an uncommon type of HF. The prevalence of this disorder is uncertain, particularly since the potential contributory role of high-output syndromes to HF may not be appreciated in many cases. Although high-output states are uncommon as a sole cause of HF, they may more commonly contribute to HF in patients with underlying cardiovascular disease and reduced myocardial reserve. (See 'Role of concurrent cardiac conditions' below.)

In a Mayo Clinic series of 120 consecutive patients with high-output HF diagnosed between 2000 and 2014, the most common causes were obesity (31 percent), liver disease (22.5 percent), arteriovenous shunts (22.5 percent), lung disease (16 percent), and myeloproliferative disorders (8 percent) [1]. This study excluded patients with physiologic (eg, pregnancy, fever, infection), iatrogenic (pulmonary vasodilator or inotrope administration), or congenital causes of high output, as well as patients with severe anemia (hemoglobin <8 mg/dL), hyperthyroidism, valvular heart disease, constrictive pericarditis, left ventricular systolic dysfunction (left ventricular ejection fraction <45 percent), cardiomyopathy, or heart transplantation.

In a study from the National Readmission Database that included nearly 5.1 million encounters, 3897 hospitalizations with high-output HF were recorded [2]. The most common causes of high-output HF were pulmonary disease (19.8 percent), obesity (9.9 percent), sepsis (9.6 percent), cirrhosis (8.9 percent), myelodysplastic syndrome (7.9 percent), hyperthyroidism (5.5 percent), and sickle cell disease (3.3 percent).

PATHOPHYSIOLOGY — High-output HF is characterized by elevated cardiac output, low systemic vascular resistance (due to peripheral vasodilation or arteriovenous shunting), and low arterial-venous oxygen content difference; some types are associated with increased oxygen consumption (reflecting increased metabolic demand). In the setting of high-output HF, the elevation in cardiac output is greater than that required to meet metabolic demand [1].

In high-output HF, low systemic vascular resistance results in borderline preserved or depressed systemic arterial blood pressure and elevated cardiac filling pressures [1]. Ineffective blood volume and pressure lead to activation of the sympathetic nervous system and renin-angiotensin-aldosterone axis and increased serum vasopressin (antidiuretic hormone) concentrations. As examples:

●In a rodent model of high-output HF, enhanced renal vascular responsiveness to angiotensin II influenced renal hemodynamics and tubular reabsorption and led to renal dysfunction [3].

●In a related preclinical model, chronic activation of catecholaminergic neurons of the rostral ventrolateral medulla promoted autonomic imbalance and cardiorespiratory dysfunction in high-output HF. This pathophysiology was reversed with inhibition of brainstem endoplasmic reticulum stress [4].

This neurohormonal activation results in increased renovascular resistance and reduced renal blood flow and glomerular filtration rate, with retention of salt and water [5]. Chronic volume overload gradually may cause ventricular enlargement, remodeling, and HF. Activation of neprilysin and the sodium-glucose co-transporter 2 have also been implicated in interstitial fibrosis and subsequent ventricular remodeling in high cardiac output states [6].

The conditions that provoke high-output HF are rarely the sole cause of HF. In most such patients, the high cardiac output provokes HF in the setting of reduced ventricular reserve (systolic and/or diastolic dysfunction) from some underlying cardiac problem. Thus, the presence of high-output HF should prompt a search for another underlying cardiovascular condition. (See 'Role of concurrent cardiac conditions' below and "Clinical manifestations, diagnosis, and management of high-output heart failure", section on 'Diagnostic evaluation'.)

CAUSES AND THEIR MECHANISMS — A number of conditions lead to an obligatory increase in cardiac output, which can precipitate HF in some patients [1,7]. While hemodynamic alterations are present across various etiologies, there are some differences among etiologies. In a series of 120 consecutive patients with high-output HF, oxygen consumption indexed to weight was highest and mixed venous oxygen content was lowest in the myeloproliferative disorder group [1]. The subgroup with liver disease had the lowest arterial-venous oxygen content difference and lowest systemic vascular resistance.

There are a variety of pathophysiologic processes that result in a high-output state. Some causes appear to have primarily peripheral vascular effects, while other causes may have metabolic effects or myocardial as well as peripheral vascular effects. The distinction between these categories is imperfect, since some causes are associated with combinations of peripheral vascular, metabolic, and myocardial effects (eg, hyperthyroidism). Peripheral vascular effects can have secondary effects on cardiac structure and function.

The prognosis of high-output HF is highly variable, as it is largely dependent upon the cause, underlying cardiovascular disease, and concurrent conditions. Overall, the mortality rate in patients with high-output HF is increased compared with controls without heart disease (eg, hazard ratio 3.4; 95% CI 1.6-7.6 compared with controls [1]). Compared with patients with HF with reduced ejection fraction, patients with high-output HF have a similar inpatient mortality rate (4.3 versus 5.2 percent; odds ratio [OR] 0.9, 95% CI 0.7-1.2) but lower 30-day readmission rate (5.7 versus 21.2 percent; OR 0.39, 95% CI 0.30-0.51) [2].

Causes grouped by predominant mechanism

Peripheral vascular effects — The following conditions with largely peripheral vascular primary effects can lead to high-output HF. Peripheral vascular effects can lead to cardiac volume overload.

Obesity — High-output HF in patients with obesity appears to be related to vasodilation, but the mechanism for vasodilation is unclear [1]. Although oxygen consumption is high in this setting, it is not elevated after adjustment for weight. The effects of obesity on the cardiovascular system may be exacerbated by pressure overload states such as hypertension [8]. Some data suggest that leptin may contribute to plasma volume expansion as well as eccentric ventricular dilatation and hypertrophy that is seen in high-output states [9]. It should also be noted that obesity is a key risk factor and distinct phenotype of HF with preserved ejection fraction, in which hemodynamic evaluation typically reveals elevated cardiac filling pressures with normal or reduced cardiac output (also known as "obesity phenotype of HFpEF") [10]. (See "Pathophysiology of heart failure with preserved ejection fraction".)

●In metabolically healthy subjects, high body mass index is associated with increased risk of diastolic dysfunction [11].

●In patients with obesity (body mass index >35 kg/m²) undergoing bariatric surgery, the presence of nonalcoholic steatohepatitis was associated with left ventricular concentric remodeling and hyperdynamic circulation [12].

Arteriovenous fistula — A large or multiple small systemic arteriovenous fistulas can cause high-output HF. A fistula can be congenital or acquired. Blood from a high-pressure artery is shunted via the arteriovenous fistula to a low-pressure vein, thus bypassing capillary beds and decreasing systemic vascular resistance. Compensatory increases in heart rate, stroke volume, and total plasma volume ensue to maintain systemic perfusion. Thus, the elevation in cardiac output associated with a fistula depends upon the size of the communication and the magnitude of the resultant reduction in systemic vascular resistance.

As described below, high-output HF in patients with chronic kidney disease most often results from an arteriovenous dialysis fistula and anemia (which is now less common due to the widespread use of erythropoietin) superimposed on underlying heart disease. Other renal etiologies include acquired intrarenal arteriovenous fistulas such as those arising as a complication following renal biopsy, renal cell carcinoma [13], and congenital renal arteriovenous malformation [14,15].

Acquired — Acquired fistulas may be caused by trauma [16], by a medical procedure (eg, surgically constructed arteriovenous access for hemodialysis or as a complication of a procedure), or by a highly vascular condition or tumor. Traumatic causes include bullet or knife wounds, especially in the thigh.

●In a systematic review of traumatic arteriovenous fistulas in 274 patients [17], the median age at presentation was 32 years and 90 percent were men. Stab wounds (43 percent) and gunshot wounds (32 percent) were the most frequent mechanism of injury; the most frequent locations were abdomen (31 percent), lower limb (29 percent), and neck (22 percent). In the 35 patients (13 percent) who presented with HF, independent predictors of HF were involvement of a large feeding artery and delayed presentation.

An aortocaval fistula may be caused by trauma or by spontaneous rupture of an aortic aneurysm [18,19].

Iatrogenic fistulas include surgically constructed arteriovenous fistulas used for access to the circulation in patients undergoing chronic hemodialysis [20-22]. An arteriovenous fistula can cause high-output HF and can also worsen pulmonary hypertension and cause right HF, as discussed separately [23]. Removal of unused arteriovenous fistulae following renal transplant may be beneficial in this setting [24,25]. For hemodialysis patients with HF, surgical revision of a high-flow arteriovenous fistula can reduce blood flow and improve cardiac function [26]. (See "Evaluation and management of heart failure caused by hemodialysis arteriovenous access" and "Pulmonary hypertension in patients with end-stage kidney disease".)

A renal arteriovenous fistula is a complication of renal biopsy, although a symptomatic fistula causing high-output HF is rare. Other cases of iatrogenic arteriovenous fistulas associated with high-output failure include an iliac arteriovenous fistula after spinal surgery [16] or abdominal surgery [27] and high-output failure following transjugular intrahepatic portosystemic shunting (TIPS) [28]. In a prospective study of 15 portal hypertensive patients, hyperdynamic circulation worsened immediately after TIPS, with a progressive adaptation over two months [29].

Arterial puncture for cardiac catheterization is an uncommon iatrogenic cause of arteriovenous fistula with an incidence of less than 1 percent of catheterizations with a transfemoral approach [30,31] and less than 0.1 percent using a transradial or transulnar approach [32,33]. High-output HF is a rare sequela of an arteriovenous fistula from cardiac catheterization with a clinical presentation ranging from two days to several months postcatheterization [34].

Skeletal disorders such as osteitis deformans (Paget disease) [35], multiple myeloma [36-38], and polyostotic fibrous dysplasia (McCune-Albright syndrome) have been identified as causes of high-output HF. Multiple minute arteriovenous fistulas in the bony lesions may cause high-output HF [38]. Extensive bone involvement (more than 20 percent of the skeleton) is required to increase the cardiac output to the point at which it may contribute to high-output problems. An additional factor for the increase in cardiac output in Paget disease may be increased cutaneous blood flow resulting from local heat production by the increased metabolic activity of affected bone. There appears to be a linear relationship between the amount of skeletal involvement and cardiac index in patients with this disease. In one study, the subgroup of patients with more extensive skeletal involvement had lower peripheral vascular resistance, higher stroke volume, and greater hydroxyproline excretion (a marker of bone turnover) [39]. (See "Clinical manifestations and diagnosis of Paget disease of bone" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

High-output HF with acquired arteriovenous fistula(s) may also be caused by a highly vascular condition or tumor such as Paget disease, Wilms' tumor [40], renal cell carcinoma [13,41,42], uterine leiomyomatosis [43], or giant placental chorioangioma [44]. Clinical manifestations of these conditions are discussed further separately. (See "Presentation, diagnosis, and staging of Wilms tumor" and "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)

Congenital — Congenital arteriovenous fistulas range from small cutaneous hemangiomas to large channel communications that can distort a limb [45]. A minority of patients with congenital fistulas have giant or multiple hemangiomas, which cause HF [46,47]. (See "Hepatic hemangioma" and "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)" and "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

Hepatic hemangiomas are typically found incidentally, with larger lesions (4 cm) more likely to present with symptoms such as abdominal pain, right upper quadrant discomfort, or fullness. Hepatic hemangiomas rarely cause high-output failure either in the setting of innumerable hemangiomas (known as hepatic hemangiomatosis) or in the setting of a giant hemangioma. Cutaneous hemangiomas may be a marker for hepatic hemangiomas. (See "Hepatic hemangioma".)

Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu disease) is characterized by hemorrhagic telangiectasias involving the mucous membranes (causing epistaxis and gastrointestinal bleeding) and skin (eg, lips, fingertips). In approximately 15 percent of affected individuals, arteriovenous malformations occur in the lung and may be associated with massive hemoptysis [48,49]. Some patients with hepatic involvement develop clinically significant arteriovenous shunts and high-output failure [50-54]. In some patients, high-output HF is the first manifestation of the disease [54], while in a subgroup of patients, clinical HF may be exacerbated by hypoxemia caused by concomitant pulmonary arteriovenous shunts [55]. Additional clinical manifestations include unexplained hematuria, hemoptysis, or family history of bleeding. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Giant cutaneous hemangiomas can also promote the development of high-output failure [56,57]. Hemangiomas are the most common tumors of infancy and seldom cause more than a cosmetic problem. Fifty percent of cutaneous lesions are present at birth; the remainder usually surface by two months of age. In rare cases, high-flow arteriovenous shunting in giant or multiple cutaneous hemangiomas can lead to the development of high-output failure [46,56,58,59]. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

Cirrhosis — Cirrhosis is associated with progressive systemic vasodilation (particularly splanchnic) and the development of intrahepatic or mesenteric arteriovenous shunts which cause increased cardiac output and low blood pressure. In a study of patients prior to liver transplantation, cirrhosis was associated with reductions in end-systolic elastance, arterial elastance, and ventriculoarterial coupling [60]. Others have shown elevated B-type natriuretic peptide levels [61]. Signs of reduced tissue perfusion include low urinary sodium excretion and increased plasma levels of the "hypovolemic" hormones renin, aldosterone, and vasopressin [62-64]. Intrapulmonary arteriovenous shunting is also observed in some patients [65]. The development of cardiac failure is insidious in these patients [66], but most die from hepatic failure prior to symptomatic heart disease. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Complications of portal hypertension' and "Hyponatremia in patients with cirrhosis", section on 'Pathogenesis'.)

Erythroderma — Erythroderma is a clinical presentation of a wide range of cutaneous and systemic diseases (including psoriasis and drug hypersensitivity reactions). The elevated cardiac output results from substantial cutaneous dilatation and an increase in blood flow to the skin. Peripheral vasodilation associated with shunting of blood flow through the skin may result in high-output HF. (See "Erythroderma in adults".)

Carcinoid syndrome — High-output HF (with low systemic vascular resistance and high cardiac output) is an atypical cardiovascular manifestation of carcinoid syndrome, which more commonly causes HF via right heart valve fibrosis [67,68]. (See "Clinical features of carcinoid syndrome" and "Carcinoid heart disease".)

Metabolic effects — The following conditions result in increased metabolic demand that may drive increases in cardiac output:

Myeloproliferative disorders — Myeloproliferative disorders (eg, myelofibrosis, polycythemia vera, and leukemia) with extramedullary hematopoiesis may cause a hypermetabolic state with increased oxygen consumption and decreased systemic vascular resistance [1]. Some patients with myelofibrosis have isolated right HF, which may be caused by the effects of circulating progenitor cells on right ventricular and pulmonary vascular function.

Hyperthyroidism — Hyperthyroidism causes high-output HF by a combination of metabolic, vascular, and direct myocardial effects. Thyroid hormone is a potent regulator of whole body metabolism; an increased circulating level of thyroxine produces an increase in metabolism accompanied by a reduction in systemic vascular resistance and an obligatory increase in cardiac output [69-72]. Hyperthyroidism may create a hyperdynamic circulatory state via enhanced sympathoadrenal activation [70,73] as well as by direct action of thyroid hormone, which possesses strong, positive chronotropic and inotropic effects [74,75]. The heart rate is increased and pulse pressure is widened. The metabolic and circulatory changes in hyperthyroid individuals are similar to those in normal volunteers during epinephrine infusion [70]. Administration of sympatholytic agents such as beta blockers to patients with hyperthyroidism can decrease the heart rate, cardiac output, and pulse pressure toward normal [70]. However, sympatholytic agents alone do not completely normalize cardiac parameters in these patients. (See "Cardiovascular effects of hyperthyroidism".)

Among patients with hyperthyroidism and HF, left ventricular ejection fraction (LVEF) may be preserved or reduced. LV systolic dysfunction may be due to tachycardia-mediated cardiomyopathy (eg, atrial fibrillation with a rapid ventricular response) or concomitant cardiac disease [76,77]. Chronic volume overload, hypercontractility, and tachycardia contribute to the development of cardiac hypertrophy in patients with hyperthyroidism [70,76,78]. It has been postulated that hyperthyroidism may have a cardiotoxic effect, perhaps mediated by beta-adrenergic stimulation [76]. Direct activation of protein-synthesizing processes by thyroid hormone may also contribute to myocardial hypertrophy. Patients with hyperthyroidism have an abnormally low or absent increase in LVEF in response to exercise [79-81]. Hyperthyroidism can also cause a hyperdynamic right ventricle that normalizes following treatment to restore a euthyroid state [82]. Reversible right ventricular failure and pulmonary hypertension has also been reported [83]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Heart failure' and "Arrhythmia-induced cardiomyopathy".)

Myocardial and peripheral vascular effects — The following conditions are postulated as having peripheral vascular effects as well as possible direct myocardial effects that may lead to high-output HF.

Sepsis — Sepsis, a clinical syndrome caused by a dysregulated inflammatory response to infection, is associated with a spectrum of hemodynamic alterations: there is frequently initial hypovolemia (prior to fluid resuscitation) with varying alterations in systemic vascular resistance and cardiac output [84,85]. Low systemic vascular resistance is frequently accompanied by high cardiac output, but patients with sepsis with HF often have reversible systolic and/or diastolic LV and/or right ventricular dysfunction, which limits cardiac reserve [84,85].

Infection leads to an inflammatory response, releasing tumor necrosis factor-alpha, interleukin-1-beta, Il-6, and other proinflammatory cytokines. These lead to systemic vasodilation and may decrease cardiac contractility via inducible nitric oxide synthase [86,87].

Beriberi — Beriberi heart disease is due to severe thiamine (vitamin B1) deficiency. The mechanism for high-output failure in beriberi may be multifactorial, with high cardiac output superimposed on myocardial dysfunction. Thiamine deficiency initially presents as a high-output state secondary to vasodilation and an increase in blood volume [88]; this is followed by eventual depression of myocardial function and the development of a low-output state [89]. The high cardiac output is due to reduced systemic vascular resistance and augmented venous return. It is not clear what causes the marked reduction in systemic vascular resistance, but it may reflect direct vasomotor depression [88].

Postmortem gross examination of the heart shows dilation without other changes. Histopathologic study shows nonspecific changes, including myocardial vacuolization and interstitial myocardial edema in the early stages, with myocyte hypertrophy, fibrosis, and cellular infiltration in the chronic phase [90]. Cardiac magnetic resonance imaging may be used to demonstrate myocardial edema in severe thiamine deficiency [91].

A biochemical lesion due to thiamine deficiency may contribute to high output and myocardial dysfunction in beriberi [92,93]. Pyruvate and lactate are important substrates for oxidation and energy production in heart muscle, but thiamine deficiency blocks their utilization. Specifically, thiamine pyrophosphate is needed for the decarboxylation of pyruvate and its subsequent oxidation in the citric acid cycle. As a result of thiamine deficiency, pyruvate and its precursor lactate build up in the blood; increased blood lactate level has been used in the diagnosis of beriberi but is nonspecific [94]. Thiamine deficiency also inhibits the function of the hexose monophosphate shunt, contributing to insufficient oxygenation of the tissues. (See "Overview of water-soluble vitamins".)

Acromegaly — Growth hormone is important for the maintenance of normal cardiac function [95]. HF is not uncommon in newly diagnosed acromegaly [96] (see "Causes and clinical manifestations of acromegaly"). In a review of 102 such patients, 10 had overt HF at the time of diagnosis [97]. Compared with those without HF, these patients had an increase in LV mass index that was largely due to chamber dilation, a reduction in LVEF (42 versus 66 percent), and a significant elevation in cardiac index (4.3 versus 3.5 L/min per m² versus 3.1 L/min per m² in controls). A contemporary, multinational registry of over 3000 patients reported low rates of cardiovascular complications (<5 percent) in adults with newly diagnosed acromegaly [98]. (See "Causes and clinical manifestations of acromegaly".)

Mitochondrial diseases — Mitochondrial diseases are a cause of high-output failure associated with lactic acidosis, reduced systemic vascular resistance caused by disturbed oxidative metabolism, and cardiomyopathy [99,100]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)

Anagrelide — Anagrelide, a phosphodiesterase III inhibitor used in the treatment of essential thrombocythemia [101], has been identified as a cause of high-output HF. Anagrelide may cause vasodilation and may also have positive inotropic and chronotropic effects. Case reports of cardiomyopathy secondary to anagrelide have also been reported [102].

Other

Anemia — Anemia has been identified as a cause of high-output HF (eg, in patients with beta-thalassemia intermedia [103,104]), but the mechanism of HF in anemia is not completely understood. Anemia, even when severe, rarely causes HF, and when it does, it is likely that the high-output failure is superimposed upon some cardiac abnormality such as valvular heart disease or underlying LV dysfunction [105]. In a seminal study involving right heart catheterization, normal cardiac hemodynamics were maintained in patients with hemoglobin values as low as 7 g/dL [106]. When the hemoglobin was 5 to 7 g/dL, cardiac output increased and HF did not occur. HF developed in the absence of underlying heart disease only with severe anemia (ie, hemoglobin less than 5 g/dL).

Decreased LV afterload secondary to reduced serum viscosity may play a role [107]. Anemia may also cause peripheral vasodilation [108] due to endothelial dysfunction [109]. The loss of hemoglobin is partly compensated for by an increase in cardiac output and widening of the arteriovenous O₂ difference. Thus, severe anemia can result in LV volume overload and increased stroke volume that can alter LV function [107]. As an example, one study of serial echocardiograms in 124 patients with sickle cell anemia found progressive chamber enlargement and increased LV mass [110]. Moreover, the LV systolic time interval and the LV pre-ejection period were progressively higher in the sickle cell group compared with same-aged controls, suggesting a decline in LV function with time.

Chronic anemia may also contribute to the development of HF from other causes. In patients with HF due to other causes, there is evidence that chronic anemia is associated with the progression of HF, but anemia is also associated with a number of common comorbidities. There is conflicting evidence regarding whether anemia is an independent cause of HF progression and worse outcomes, or if it is simply associated with overall disease severity. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

Chronic pulmonary disease — Chronic pulmonary disease with associated hypoxia and hypercapnia is associated with high-output HF, which may be caused by reduced systemic vascular resistance, salt and water retention, and impaired renal blood flow [1]. Some patients with high-output HF associated with lung disease present with isolated right HF, which may be secondary to hypoxic pulmonary vasoconstriction with systemic arterial vasodilation [1].

Additional precipitants of high output — There are a number of physiologic conditions that can substantially increase cardiac output and contribute to a high-output state that may precipitate HF:

●Physical or emotional stress – Stress may provoke a state of catecholamine excess with increased cardiac output and variable effects on systemic vascular resistance.

●Exercise – With exercise, cardiac output increases, and systemic vascular resistance generally decreases. (See "Exercise physiology".)

●Fever – Fever increases metabolic demand and produces vasodilation, especially in the skin. Resolution of the fever is accompanied by a reduction in cardiac output to normal.

●Hot climate – A hot, and especially humid, environment increases cardiac output through mechanisms similar to fever [111].

●Pregnancy is associated with increased metabolic demand, increased blood volume, placental blood flow (which may act as an arteriovenous shunt), reduced systemic vascular resistance, elevated maternal heart rate (by 15 to 20 beats per minute), and increased resting cardiac output (by 30 to 50 percent above baseline). (See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)

These hemodynamic changes may precipitate HF in pregnant women with an underlying cardiac disorder or who develop peripartum cardiomyopathy [112]. Women with an underlying cause for a high cardiac output, such as an arteriovenous fistula, hereditary telangiectasia, or anemia, are more likely to develop high-output HF during pregnancy [113-116]. In addition, multiple pregnancies in a patient with underlying fistulas may progressively exacerbate vascular malformations and lead to the development of HF despite a history of previous uncomplicated pregnancies. (See "Management of heart failure during pregnancy".)

Role of concurrent cardiac conditions — Causes contributing to high cardiac output are rarely the sole cause of HF; in most patients with high-output HF, HF is provoked by high output in the setting of reduced ventricular reserve (systolic and/or diastolic dysfunction) from some underlying cardiac problem. Examples include patients with:

●Severe functional tricuspid regurgitation – In a study of 132 patients undergoing transcatheter tricuspid valve repair, patients with high cardiac index (>2.6 L/min/m²) were characterized by larger inferior vena cava diameters, reduced liver function, higher incidence of ascites, and markedly reduced systemic vascular resistance [117]. Postprocedure, these patients were more likely to have persistent signs of right ventricular dysfunction (ie, elevated right atrial pressures and right ventricular enlargement) and a higher risk of mortality (42 versus 20 percent in the group with intermediate cardiac output; adjusted hazard ratio 4.7, 95% CI 1.8-13.0).

●Failing Fontan circulation – In a study of 139 adults with a Fontan circulation (extracardiac conduit or lateral tunnel), the subgroup of patients (n = 11) with portosystemic venous shunts had increased cardiac index (5.3 L/min/m²) and decreased systemic vascular resistance (7.1 Wood units) [118].

In another small series of failing Fontan patients with high cardiac output, vasoconstrictor therapy with intravenous norepinephrine and/or oral midodrine increased systolic blood pressure, arterial oxygen saturation, and systemic vascular resistance and decreased hospital readmissions [119].

Thus, the presence of high-output HF should prompt a search for another underlying cardiovascular condition, including a search for acquired arteriovenous fistulas.

In some clinical settings, multiple factors may contribute to the development of HF. As an example, in patients with end-stage kidney disease who have high-output HF related to hemodialysis, arteriovenous access, anemia (which is now less common due to the widespread use of erythropoietin), and volume expansion (due to salt and water retention) caused by kidney disease may contribute to the high-output state. As an example:

●In a study of 140 patients receiving outpatient dialysis therapy, arteriovenous fistula flow was positively associated with an upper arm fistula, body mass index, and N-terminal pro-B-type natriuretic peptide level and negatively associated with diabetes [120]. Notably, high arteriovenous fistula flow was not associated with extracellular volume in this cohort.

Premature atherosclerosis and LV hypertrophy due to hypertension are common in patients with end-stage kidney disease. Thus, patients with end-stage kidney disease frequently have heart disease with increased susceptibility to HF in the setting of an elevated cardiac output. Another example of multiple factors causing HF is high-output HF caused by the combination of morbid obesity plus cirrhosis due to nonalcoholic fatty liver disease. (See "Evaluation and management of heart failure caused by hemodialysis arteriovenous access" and "Overview of screening and diagnosis of heart disease in patients on dialysis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

●High-output heart failure (HF) is an uncommon type of HF. The prevalence of this disorder is uncertain, particularly since the potential contributory role of high-output syndromes to HF may not be appreciated in many cases. Although high-output states are uncommon as a sole cause of HF, they may more frequently contribute to HF in patients with underlying cardiovascular disease and reduced myocardial reserve. (See 'Epidemiology' above.)

●High-output HF is characterized by elevated cardiac output, low systemic vascular resistance (due to peripheral vasodilation or arteriovenous shunting), and low arterial-venous oxygen content difference; some types are associated with increased oxygen consumption (reflecting increased metabolic demand). In the setting of high-output HF, the elevation in cardiac output is greater than that required to meet metabolic demand. (See 'Pathophysiology' above.)

●There are a variety of pathophysiologic processes that result in a high-output state. Some causes appear to have primarily peripheral vascular effects, while other causes may have metabolic effects or myocardial as well as peripheral vascular effects. The distinction between these categories is imperfect since some causes are associated with combinations of peripheral vascular, metabolic, and myocardial effects (eg, hyperthyroidism, beriberi). Peripheral vascular effects can have secondary effects on cardiac structure and function. (See 'Causes and their mechanisms' above.)

•Morbid obesity, arteriovenous fistula, cirrhosis, erythroderma, and carcinoid syndrome are among the causes of high-output HF with peripheral vascular effects. (See 'Peripheral vascular effects' above.)

•Myeloproliferative disorders and hyperthyroidism are causes of high-output HF associated with increased metabolic demand.

•Sepsis, beriberi, acromegaly, and mitochondrial diseases are causes of high-output HF with myocardial and peripheral vascular effects.

•Other causes of high-output HF include anemia and chronic pulmonary disease.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Amir Haghighat, MD, FACC, who contributed to earlier versions of this topic review.